TMIC-116. Divergent Microglial Lipid Metabolism Underlies Sex Bias in Neural Development and Medulloblastoma

Abstract Pediatric brain tumors are among the leading causes of cancer-related death in children, with treatment options remaining limited and a consistent male predominance in both incidence and outcomes. However, the developmental and mechanistic basis for these sex differences remains poorly understood. Here, we use medulloblastoma (MB)—the most common malignant pediatric brain tumor—as a model to uncover how sex-specific cellular and microenvironmental interactions contribute to this disparity. Through integrated single-cell transcriptomic analyses of developing human and mouse cerebella, combined with in vitro and in vivo validation studies, we reveal intrinsic sexual dimorphisms in neural progenitor cells (NPCs). These differences are driven in part by microglia-mediated erythrophagocytosis and lipid metabolism. Specifically, male erythrocytes express lower levels of Glycophorin A (GYPA), resulting in increased erythrocyte fragility and subsequent phagocytosis by microglia. In turn, male microglia show elevated Biliverdin Reductase B (BLVRB) and reduced ATP Binding Cassette A1 (ABCA1) expression, disrupting bilirubin-lipid metabolic balance and impairing lipid transfer to NPCs. This metabolic inefficiency leads to delayed NPC differentiation and maturation in males, increasing their vulnerability to oncogenic transformation and promoting higher MB incidence and metastasis. These findings identify a sex-specific mechanism by which altered erythrocyte-microglia-NPC interactions influence cerebellar development and tumor susceptibility. Together, this study provides critical insights into the developmental origins of sex differences in pediatric brain tumors and reveals novel, sex-informed targets for future therapeutic strategies.